We read with interest the study by Dr. Tedeschi and colleagues [1] which reported that patients with at least one episode of acute Calcium pyrophosphate (CPP) crystal arthritis had increased the risk of short (0-2 year) and long-term (2-10 year) non-fatal CV events compared with those without evidence of this acute crystalline arthritis. However, acute CPP crystal arthritis did not confer increased risk for all-cause mortality. This study focuses on an episode of acute calcium pyrophosphate (CPP) crystal arthritis as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
First, epidemiologists agree that several clinical risk factors are associated with cardiovascular outcome, including acute cerebrovascular insufficiency, hyperparathyroidism, and phenotypes of CPP disease [2,3]. However, the authors did not exclude people with these risk factors, and an evaluation of these risk factors was not presented. The confounding effect of these variables may have contributed to the significant effect in causing cardiovascular disease.
Second, it reported that longer disease duration of CPP crystal arthritis have also been considered to carry an elevated risk for cardiovascular disease [4]. Previous studies have clearly demonstrated that chronic CPP crystal arthritis did confer increased risk for myocardial infarction, acute coronary syndrome, and stroke[5]. However, the duration of CPP...
We read with interest the study by Dr. Tedeschi and colleagues [1] which reported that patients with at least one episode of acute Calcium pyrophosphate (CPP) crystal arthritis had increased the risk of short (0-2 year) and long-term (2-10 year) non-fatal CV events compared with those without evidence of this acute crystalline arthritis. However, acute CPP crystal arthritis did not confer increased risk for all-cause mortality. This study focuses on an episode of acute calcium pyrophosphate (CPP) crystal arthritis as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
First, epidemiologists agree that several clinical risk factors are associated with cardiovascular outcome, including acute cerebrovascular insufficiency, hyperparathyroidism, and phenotypes of CPP disease [2,3]. However, the authors did not exclude people with these risk factors, and an evaluation of these risk factors was not presented. The confounding effect of these variables may have contributed to the significant effect in causing cardiovascular disease.
Second, it reported that longer disease duration of CPP crystal arthritis have also been considered to carry an elevated risk for cardiovascular disease [4]. Previous studies have clearly demonstrated that chronic CPP crystal arthritis did confer increased risk for myocardial infarction, acute coronary syndrome, and stroke[5]. However, the duration of CPP crystal arthritis was not captured in this study, which may have impacted the risk for non-fatal CV events in patients with acute CPP crystal arthritis.
In conclusion, although we have some concerns about the study by Tedeschi et al.[1], we applaud the authors for their commendable work and hope that this study will benefit readers. We look forward to further work on the important topic of early prevention for cardiovascular diseases in patients with acute CPP crystal arthritis and hope that early preventive application for CV events will benefit high-risk people.
Contributors All authors reviewed the draft and approved the submission of the manuscript.
Competing interests None declared.
References:
1. Tedeschi SK, Huang W, Yoshida K, et al. Risk of cardiovascular events in patients having had acute calcium pyrophosphate crystal arthritis. Ann Rheum Dis 2022;81:1323-9.
2. Cheremushkina E, Eliseev M, Sheliabina O, et al. Effect of colchicine therapy on atherosclerosis-related cardiovascular outcome in patients with calcium pyrophosphate crystal deposition disease. Ann Rheum Dis 2022;8(Suppl 1):382.
3. Toussirot E, Marotte H, Mulleman D, et al.Increased high molecular weight adiponectin and lean mass during tocilizumab treatment in patients with rheumatoid arthritis: a 12-month multicentre study. Arthritis Res Ther 2020;22:224.
4. Bashir M, Sherman KA, Solomon DH, et al. Cardiovascular disease risk in calcium pyrophosphate deposition disease: a nationwide study of Veterans. Arthritis Care Res 2021;73:24783.
5. Wang H, Bai J, He B, et al. Osteoarthritis and the risk of cardiovascular disease: a meta-analysis of observational studies. Sci Rep 2016;6:39672.
To the Editor
We recently have read the article written by Dr. Daien et al. entitled published in Annals of the Rheumatic Diseases in 31th of May, 2022 (1). The study assessed the effect of different doses of ABX464 on clinical and laboratory features of patients with active rheumatoid arthritis (RA) and the rate of development of treatment-emergent adverse events in these patients. In this study, it was showed that each day 50 mg use of ABX464 could exert beneficial effects in the patients with acceptable safety and tolerability profile. This study provides fascinating evidence regarding the use of this first-in-class drug candidate for patients not responding to more frequently used treatment regimens; however, there are some points that we would like to address.
The authors mentioned that patients with moderate to severe RA who had rheumatoid factor, anticitrullinated peptide antibody or bone erosions were recruited in the study. The study aimed at comparison of rate of response to the treatment and development of adverse events in each arm of the study. Although, it is generally considered that the randomized design of the clinical studies would produce comparable groups and result in unbiased assessment of the outcomes, different factors which were previously identified in the literature that could be in association with severity of rheumatoid arthritis or poor response to the treatment should had been considered in the quantitative analysis of this study....
To the Editor
We recently have read the article written by Dr. Daien et al. entitled published in Annals of the Rheumatic Diseases in 31th of May, 2022 (1). The study assessed the effect of different doses of ABX464 on clinical and laboratory features of patients with active rheumatoid arthritis (RA) and the rate of development of treatment-emergent adverse events in these patients. In this study, it was showed that each day 50 mg use of ABX464 could exert beneficial effects in the patients with acceptable safety and tolerability profile. This study provides fascinating evidence regarding the use of this first-in-class drug candidate for patients not responding to more frequently used treatment regimens; however, there are some points that we would like to address.
The authors mentioned that patients with moderate to severe RA who had rheumatoid factor, anticitrullinated peptide antibody or bone erosions were recruited in the study. The study aimed at comparison of rate of response to the treatment and development of adverse events in each arm of the study. Although, it is generally considered that the randomized design of the clinical studies would produce comparable groups and result in unbiased assessment of the outcomes, different factors which were previously identified in the literature that could be in association with severity of rheumatoid arthritis or poor response to the treatment should had been considered in the quantitative analysis of this study. The presence of comorbidities, smoking and ethnicity are among these factors that are associated with the response to treatment (2, 3). The participants enrolled in this study were from 21 centers from 4 countries which raises concern toward the potential for bias as ethnicity was not considered in the study. Besides, patient-reported symptoms, outcomes and true disease state have also been shown to be associated with social status of the patient, educational level, health literacy and presence of comorbidities and ethnicity (4, 5). Therefore, considering these potential confounding factors and performing appropriate techniques for adjusting of them lower the source of bias and increase the credibility of the findings in the study.
Second, the significance level considered in this study was 10 percent. This error rate is typically considered to 5 percent, especially when the efficacy of a new drug class is being assessed in clinical studies (6). Although this high cut off for type Ⅰ error could be justified by the authors based on the intrinsic issues of the study, they should have mentioned and addressed it in the article. Third, in the protocol of this study (NCT03813199), it was mentioned that 24 centers were chosen for participants enrollment; however, in the main text of the article, the authors stated that the study was conducted in 21 centers. The detail of this issue that 2 centers in Czechia and one center in Belgium were not considered in the study should be discussed in the article to avoid any concern regarding the potential bias of selective reporting.
Notwithstanding the foregoing, this study has provided first evidence on the efficacy and safety of this first-in-class drug in patients with moderate to severe RA nonresponding to methotrexate or anti-tumor necrosis factor-α agents. However, whether to administrate this drug or not requires further studies with larger sample size and longer duration of follow-up. Also, there is needs for conducting studies to compare efficacy and safety of this drug class with more frequently used therapeutic options in patients with RA who are not responding to first line treatments as there are other available treatment strategies in these patients.
Authors’ contributions: Both authors contributed in all processes of the preparation of this paper.
Acknowledgement: None.
Conflict of Interest statement: Authors declare no conflict of interests.
Funding: None.
Patient and Public Involvement: Patients or the public were not involved in the design, or conduct, or reporting, or dissemination plans of our research
References
1. Daien C, Krogulec M, Gineste P, Steens J-M, Desroys du Roure L, Biguenet S, et al. Safety and efficacy of the miR-124 upregulator ABX464 (obefazimod, 50 and 100 mg per day) in patients with active rheumatoid arthritis and inadequate response to methotrexate and/or anti-TNFα therapy: a placebo-controlled phase II study. 2022;81(8):1076-84.
2. de Hair MJH, Jacobs JWG, Schoneveld JLM, van Laar JM. Difficult-to-treat rheumatoid arthritis: an area of unmet clinical need. Rheumatology. 2017;57(7):1135-44.
3. Albrecht K, Zink A. Poor prognostic factors guiding treatment decisions in rheumatoid arthritis patients: a review of data from randomized clinical trials and cohort studies. Arthritis Research & Therapy. 2017;19(1):68.
4. Katz PP, Barton J, Trupin L, Schmajuk G, Yazdany J, Ruiz PJ, et al. Poverty, Depression, or Lost in Translation? Ethnic and Language Variation in Patient-Reported Outcomes in Rheumatoid Arthritis. Arthritis care & research. 2016;68(5):621-8.
5. Tan Y, Buch MH. 'Difficult to treat' rheumatoid arthritis: current position and considerations for next steps. 2022;8(2):e002387.
6. Confirmatory clinical trials : Analysis of categorical efficacy data.
Glucocorticoid (GC) therapy is still the mainstay in managing rheumatoid arthritis (RA). The benefits of low-dose GC therapy are well established after decades of clinical experience in RA. Yet, it is essential to appoint the danger of exposure to chronic GC therapy.
For many patients with RA and other inflammatory rheumatic musculoskeletal diseases (RMD), starting prednisolone means taking glucocorticoids for several years or decades, often indefinitely.1 The long-term complications of GC therapy are rarely emphasised by most clinical trials that usually run for only 1 or 2 years. In this regard, the GLORIA trial2 has illuminated both the harms and benefits of 2-year low-dose (5 mg daily) prednisolone in 451 elderly patients (≥65 years) with moderately active established RA. Indeed, there was an 11% increase in patients with at least one adverse event (AE) of special interest (mainly mild to moderate infections) in the prednisolone arm, accounting for a 1.24 (95% CL 0.4) fold higher risk compared to placebo, just within two years of treatment.2
The likelihood of major osteoporotic fractures in GC users increases with the dosage, but more importantly, with the cumulative dose and duration of GC therapy.3 Moreover, low-dose GC therapy (≤5 mg/day) did not seem to be associated with a reduction of bone mineral density (BMD) in patients with inflammatory RMD and current or prior exposure to GC.4 However, while GC therapy effectively alleviates inflammation, it has...
Glucocorticoid (GC) therapy is still the mainstay in managing rheumatoid arthritis (RA). The benefits of low-dose GC therapy are well established after decades of clinical experience in RA. Yet, it is essential to appoint the danger of exposure to chronic GC therapy.
For many patients with RA and other inflammatory rheumatic musculoskeletal diseases (RMD), starting prednisolone means taking glucocorticoids for several years or decades, often indefinitely.1 The long-term complications of GC therapy are rarely emphasised by most clinical trials that usually run for only 1 or 2 years. In this regard, the GLORIA trial2 has illuminated both the harms and benefits of 2-year low-dose (5 mg daily) prednisolone in 451 elderly patients (≥65 years) with moderately active established RA. Indeed, there was an 11% increase in patients with at least one adverse event (AE) of special interest (mainly mild to moderate infections) in the prednisolone arm, accounting for a 1.24 (95% CL 0.4) fold higher risk compared to placebo, just within two years of treatment.2
The likelihood of major osteoporotic fractures in GC users increases with the dosage, but more importantly, with the cumulative dose and duration of GC therapy.3 Moreover, low-dose GC therapy (≤5 mg/day) did not seem to be associated with a reduction of bone mineral density (BMD) in patients with inflammatory RMD and current or prior exposure to GC.4 However, while GC therapy effectively alleviates inflammation, it has a devastating effect on bone.5 Indeed, it is hard to estimate the risk of major osteoporotic fractures from glucocorticoid-induced osteoporosis (GIOP) using dual X-ray absorptiometry (DXA), as frailty fractures occur with normal or osteopenic BMD in many patients with GIOP. It is also worrisome that GIOP is often overlooked since only 13% of elderly patients with a diagnosis of osteoporosis received antiresorptive drugs despite initiating GC therapy.2 Moreover, minor complaints of ecchymosis, haematoma and skin atrophy are more common amongst long-dose GC users2 but highly relevant to their quality of life.
In our cohort of 1366 RA patients actively treated with biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), those older than 65 years represent almost 50% of the treated population. However, the risks of low-dose GC therapy in older RA patients taking b/tsDMARDs have received only a little attention. No randomised controlled trial has investigated the safety of low-dose GC in RA patients taking b/tsDMARDs. In the GLORIA trial, one of the few randomised controlled trials of low-dose GC therapy in RA, only 16% and 13% of patients took biologics at baseline in the prednisolone and placebo groups, respectively, and just ≃6% of participants per group initiated or switched to biological DMARDs during follow-up.2 Patients with RA included in the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis were at higher risk for nonserious infections if treated concomitantly with GC therapy (hazard ratio 1.25, 95% CI 1.19–1.32).6 One more extensive cohort study from the United States found similar higher risks for severe infection in patients receiving low-dose GC (≤5 mg daily) in addition to a b/tsDMARD (adjusted HR 1.26, 95% CI 1.20–1.33) or methotrexate without a b/tsDMARD (adjusted HR 1.32, 95% CI 1.26–1.37), compared to not using glucocorticoids.7
In conclusion, there is a need for more data to determine the long-term (>2 years) balance between efficacy and harms of low-dose GC therapy for patients with RA.
References
1. Giollo A, Rossini M, Bettili F, et al. Permanent Discontinuation of Glucocorticoids in Polymyalgia Rheumatica Is Uncommon but May Be Enhanced by Amino Bisphosphonates. J Rheumatol 2019;46:318-322.
2. Boers M, Hartman L, Opris-Belinski D for the GLORIA Trial consortium et al. Low dose, add-on prednisolone in patients with rheumatoid arthritis aged 65+: the pragmatic randomised, double-blind placebo-controlled GLORIA trial. Ann Rheum Dis 2022;81:925-936.
3. Abtahi S, Driessen JHM, Burden AM, et al. Low-dose oral glucocorticoid therapy and risk of osteoporotic fractures in patients with rheumatoid arthritis: a cohort study using the Clinical Practice Research Datalink. Rheumatology (Oxford) 2022;61:1448-1458.
4. Wiebe E, Huscher D, Schaumburg D, et al. Optimising both disease control and glucocorticoid dosing is essential for bone protection in patients with rheumatic disease. Ann Rheum Dis 2022 Jun 9:annrheumdis-2022-222339.
5. Takahata M, Shimizu T, Yamada S, et al. Bone biopsy findings in patients receiving long-term bisphosphonate therapy for glucocorticoid-induced osteoporosis. J Bone Miner Metab 2022;40:613-622.
6. Bechman K, Halai K, Yates M, et al. Nonserious Infections in Patients With Rheumatoid Arthritis: Results From the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis. Arthritis Rheumatol 2021;73:1800-1809.
7. George MD, Baker JF, Winthrop K, et al. Risk for Serious Infection With Low-Dose Glucocorticoids in Patients With Rheumatoid Arthritis: A Cohort Study. Ann Intern Med 2020;173:870-878.
Bandak et al.[1] recently published a paper comparing the effect of an exercise and education program with an open-label placebo on a range of outcomes for people with knee osteoarthritis (OA). The exercise and education program consisted of two weeks of 1x1.5 hour education sessions/ week, then six weeks of 2x1 hour exercise sessions/ week. The open-label placebo involved four fortnightly knee intra-articular saline injections and arthrocentesis (if required).[1] The authors argued “open-label placebo provides an opportunity to compare exercise and education with an inert comparator and thereby mitigate some of the inbuilt challenges with blinded comparator groups in clinical trials of exercise and education.” However, the use of an open-label placebo does not attempt to facilitate any opportunity for blinding, and their ‘placebo’ intervention does not meet established placebo criteria.
Placebo interventions should have no therapeutic effect, and should be perceived to be identical to the intervention of interest,[2] to control for the placebo effect; neither of these criteria has been met by Bandak et al.’s[1] placebo. Although saline injections are pharmacologically inert, they may have a real therapeutic effect particularly when coupled with arthrocentesis, as they may exert specific physical and chemical effects that could improve symptoms.[3] As such, it has been recommended that saline intra-articular injections not be used as placebo interventions in studi...
Bandak et al.[1] recently published a paper comparing the effect of an exercise and education program with an open-label placebo on a range of outcomes for people with knee osteoarthritis (OA). The exercise and education program consisted of two weeks of 1x1.5 hour education sessions/ week, then six weeks of 2x1 hour exercise sessions/ week. The open-label placebo involved four fortnightly knee intra-articular saline injections and arthrocentesis (if required).[1] The authors argued “open-label placebo provides an opportunity to compare exercise and education with an inert comparator and thereby mitigate some of the inbuilt challenges with blinded comparator groups in clinical trials of exercise and education.” However, the use of an open-label placebo does not attempt to facilitate any opportunity for blinding, and their ‘placebo’ intervention does not meet established placebo criteria.
Placebo interventions should have no therapeutic effect, and should be perceived to be identical to the intervention of interest,[2] to control for the placebo effect; neither of these criteria has been met by Bandak et al.’s[1] placebo. Although saline injections are pharmacologically inert, they may have a real therapeutic effect particularly when coupled with arthrocentesis, as they may exert specific physical and chemical effects that could improve symptoms.[3] As such, it has been recommended that saline intra-articular injections not be used as placebo interventions in studies of knee OA.[3] Bandak et al.’s[1] use of saline intra-articular injections as a placebo intervention was inappropriate.
Although Bandak et al.[1] argued that by using an open-label placebo they controlled for the placebo effect, this is not the case. In addition to the abovementioned concerns regarding the real therapeutic effect of a saline intra-articular injection, by design the placebo intervention would have been perceived as different by participants who would be aware of the two treatments by the provision of their informed consent. Furthermore, researchers told participants that saline injections were “inert, yet with potential beneficial effects that may compare to those of exercise and education”, and that “investigators had no treatment preference”[1] in an attempt to make the placebo effect comparable. These statements may have negatively influenced the patient-reported outcomes for those in the education and exercise intervention group, as the researchers implied they anticipated no real effect. As a result, the open-label placebo has not controlled for the placebo effect, as implied by the authors.
The findings of Bandak et al.’s[1] study must be considered with caution, and we should not be swayed by the inappropriate use of the term ‘placebo’. Placebo-controlled trials are often considered the ‘gold standard’ when the aim is to compare an intervention with no intervention. However, if the chosen ‘placebo intervention’ does not meet the necessary criteria for a placebo, such studies provide misleading evidence that could lead to inappropriate management recommendations for knee OA, including negative perceptions about the value of education and exercise programs.
Bandak et al.[1] concluded that the pain and function results were equivalent between their treatment and placebo groups, stating that their “findings raise important questions about … the continued widespread recommendation of exercise and education in the management of knee OA.” We do not find their conclusion valid. Instead of aiming for (potentially invalid) placebo controls, we should be making meaningful comparisons that can guide therapy: for instance, studies that compare different education and exercise programs, compare such programs with treatment as usual or in addition to treatment as usual, would more directly inform positive case management.
References
1. Bandak E, Christensen R, Overgaard A, et al. Exercise and education versus saline injections for knee osteoarthritis: a randomised controlled equivalence trial. Ann Rheum Dis 2022;81(4):537-43. doi: 10.1136/annrheumdis-2021-221129
2. Fitzgerald GK, Hinman RS, Zeni Jr J, et al. OARSI Clinical Trials Recommendations: Design and conduct of clinical trials of rehabilitation interventions for osteoarthritis. Osteoarthritis Cartilage 2015;23(5):803-14. doi: 10.1016/j.joca.2015.03.013
3. Fazeli MS, McIntyre L, Huang Y, et al. Intra-articular placebo effect in the treatment of knee osteoarthritis: a survey of the current clinical evidence. Ther Adv Musculoskelet Dis 2022;14: 1759720X211066689. doi: 10.1177/1759720X211066689
The Impact of Clinical Setting on ANA Responses in SLE: Comment on the article by Choi et al.
David S. Pisetsky1 2 and Peter E. Lipsky3 4
1 Medical Research Service, Durham VA Medical Center, Durham, North Carolina, USA
2 Departments of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina, USA
3 RILITE Foundation, Charlottesville, Virginia, USA
4 AMPEL BioSolutions LLC, Charlottesville, Virginia, USA
In a recent paper in the Annals of the Rheumatic Diseases, Choi et al report data on the expression of antinuclear antibodies (ANA) in the sera of patients with systemic lupus erythematosus (SLE).(1) Using a large cohort of well characterized patients from the SLICC (Systemic Lupus International Cooperating Clinics) consortium, the authors show that ANA expression is almost invariable in SLE using three ANA assays (two immunofluorescence or IFA and one ELISA); over time, some changes can occur, with the ELISA showing a greater reduction in the frequency of positive responses than the IFA assays. In this study, patients were early in disease, with the first sample obtained on average 0.58 years after diagnosis.
Choi et al are to be congratulated for this detailed and comprehensive study that includes longitudinal data. Most other studies on ANA expression in SLE have been cross-sectional in design or involved longitudinal data of relatively few patients.(2) Nevertheless, while consistent with data und...
The Impact of Clinical Setting on ANA Responses in SLE: Comment on the article by Choi et al.
David S. Pisetsky1 2 and Peter E. Lipsky3 4
1 Medical Research Service, Durham VA Medical Center, Durham, North Carolina, USA
2 Departments of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina, USA
3 RILITE Foundation, Charlottesville, Virginia, USA
4 AMPEL BioSolutions LLC, Charlottesville, Virginia, USA
In a recent paper in the Annals of the Rheumatic Diseases, Choi et al report data on the expression of antinuclear antibodies (ANA) in the sera of patients with systemic lupus erythematosus (SLE).(1) Using a large cohort of well characterized patients from the SLICC (Systemic Lupus International Cooperating Clinics) consortium, the authors show that ANA expression is almost invariable in SLE using three ANA assays (two immunofluorescence or IFA and one ELISA); over time, some changes can occur, with the ELISA showing a greater reduction in the frequency of positive responses than the IFA assays. In this study, patients were early in disease, with the first sample obtained on average 0.58 years after diagnosis.
Choi et al are to be congratulated for this detailed and comprehensive study that includes longitudinal data. Most other studies on ANA expression in SLE have been cross-sectional in design or involved longitudinal data of relatively few patients.(2) Nevertheless, while consistent with data underpinning the designation of a positive ANA in the EULAR-ACR classification system, the conclusions of the study pertain only to the three assays used.
The performance characteristics of ANA testing are relevant, indeed, crucial, in two disparate settings: patient classification and assessment of eligibility of patients for clinical trials. The frequencies of ANA positivity in these two settings may be very different because of the features of the patient populations studied. Classification (or diagnosis) usually involves early disease; the clinical trial setting usually involves patients later in disease course and therefore extended periods of treatment.
As shown most pertinently in studies with belimumab, many patients at the time of screening for trial eligibility have a high frequency of ANA negativity.(3) These studies also showed that treatment responses can vary depending on serological status, with patients who are ANA positive more likely to respond than those who are serologically negative. These findings led to the current approach for serological testing in the trial setting, with eligibility dependent on serological positivity in terms of tests for ANAs by IFA, anti-DNA and/or anti-Sm.(4, 5)
The lower frequency of ANA positivity in patients considered for clinical trials has a number of possible explanations including the performance characteristics of the assays used. Our previous study showed that different assays can lead to widely varying frequencies of ANA positivity in cross-sectional studies of patients followed in a university setting as well as patients enrolled in a clinical trial.(6, 7) Pending more data on the results of different ANA kits in both the classification and clinical trial settings, it seems reasonable that studies involving ANA testing specify the kit used and relevant data about the frequency of responses in patients with SLE and control populations.
Another factor that may influence the frequency of ANA positivity in any lupus population is disease duration. The study of Choi et al demonstrated a decline in the frequency of ANA positivity over time. The time-frame for this study was only 5 years, however, meaning that most patients had shorter disease duration than in the clinical trial setting. In the trial of anifrolumab, for example, the placebo population had a median time from diagnosis of 78.0 months (range 6-494) whereas the treatment group had a median time of 94.5 months (range 6-555).(8)
The study of Choi et al indicates the persistence of ANA responses within a few years of diagnosis; this observation, however, should not obscure the equally important point that ANA levels can change significantly in response to therapy. The time course of anti-DNA expression clearly illustrates the mutability of ANA responses with treatment. The effects of belimumab are another example of the impact of treatment on ANA levels since this agent can lower autoantibody levels by up to approximately 50%.(4, 9) Other agents used to treat SLE also have effects on B cell number and function that could decrease ANA expression. These agents include cyclophosphamide, rituximab and mycophenolate among commonly used agents, although the effects of these agents can differ with respect to B cell subpopulations, plasmablasts and plasma cells.(10-13)
In studies on the effects of various immunomodulatory therapies, it is important to note that some autoantibodies (e.g., anti-DNA) can show decreases out of proportion to the effects of total Ig levels. While other ANAs such as anti-Sm or anti-RNP can show decreases perhaps not as profound as anti-DNA, anti-Ro antibody may not be affected by belimumab, for example.(9) The maintenance of a consistent level of antibody production could suggest production by long-lived plasma cells. An intriguing study by Lindop et al showed that the anti-Ro response, while showing little change in levels over time, resulted from the emergence of new clones as indicated by variable region sequences.(14) In this case, the stability in levels of the ANA gave a false impression of an origin from long-lived plasma cells, whereas the clonal diversification implicates ongoing tick-over from memory B cells.
Given the range of new therapies under investigation for SLE, it is important to recognize the unique immunological features of the clinical trial population (i.e., longer disease duration, history of previous immunosuppressive agents, active disease) and develop a serological profile of this patient population with quantitative assays and optimally a range of different testing kits. The study by Choi is an important step in exploring the immune landscape of SLE in the first years after disease onset. In view of advances in serological testing and future clinical trials, further exploration of this landscape in subsequent years will be both fascinating and essential.
1. Choi MY, Clarke AE, Urowitz M, et al. Longitudinal analysis of ANA in the Systemic Lupus International Collaborating Clinics (SLICC) Inception Cohort. Ann Rheum Dis 2022.
2. Frodlund M, Wetterö J, Dahle C, et al. Longitudinal anti-nuclear antibody (ANA) seroconversion in systemic lupus erythematosus: a prospective study of Swedish cases with recent-onset disease. Clin Exp Immunol 2020;199(3):245-54.
3. Wallace DJ, Stohl W, Furie RA, et al. A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum 2009;61(9):1168-78.
4. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum 2011;63(12):3918-30.
5. Pisetsky DS, Rovin BH, Lipsky PE, et al. New Perspectives in Rheumatology: biomarkers as entry criteria for clinical trials of new therapies for systemic lupus erythematosus: the example of antinuclear antibodies and anti-DNA. Arthritis Rheumatol 2017;69:487-93.
6. Pisetsky DS, Spencer DM, Lipsky PE, et al. Assay variation in the detection of antinuclear antibodies in the sera of patients with established SLE. Ann Rheum Dis 2018;77(6):911-3.
7. Pisetsky DS, Thompson DK, Wajdula J, et al. Variability in Antinuclear Antibody Testing to Assess Patient Eligibility for Clinical Trials of Novel Treatments for Systemic Lupus Erythematosus. Arthritis Rheumatol 2019;71(9):1534-8.
8. Morand EF, Furie R, Tanaka Y, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med 2020;382(3):211-21.
9. Parodis I, Åkerström E, Sjöwall C, et al. Autoantibody and Cytokine Profiles during Treatment with Belimumab in Patients with Systemic Lupus Erythematosus. Int J Mol Sci 2020;21(10).
10. Eickenberg S, Mickholz E, Jung E, et al. Mycophenolic acid counteracts B cell proliferation and plasmablast formation in patients with systemic lupus erythematosus. Arthritis Res Ther 2012;14(3).
11. Heidt S, Roelen DL, Eijsink C, et al. Effects of immunosuppressive drugs on purified human B cells: evidence supporting the use of MMF and rapamycin. Transplantation 2008;86(9):1292-300.
12. Karnell JL, Karnell FG, 3rd, Stephens GL, et al. Mycophenolic acid differentially impacts B cell function depending on the stage of differentiation. J Immunol 2011;187(7):3603-12.
13. Fassbinder T, Saunders U, Mickholz E, et al. Differential effects of cyclophosphamide and mycophenolate mofetil on cellular and serological parameters in patients with systemic lupus erythematosus. Arthritis Res Ther 2015;17(1):92.
14. Lindop R, Arentz G, Bastian I, et al. Long-term Ro60 humoral autoimmunity in primary Sjögren's syndrome is maintained by rapid clonal turnover. Clin Immunol 2013;148(1):27-34.
We read with great interest the article titled ‘Colchicine prophylaxis is associated with fewer gout flares after COVID-19 vaccination’ by Lu et al.1. The authors found that COVID-19 vaccination was associated with increased odds of gout flare and was negatively associated with colchicine prophylaxis. However, we would like to draw attention to some concerns.
First, it is problematic to present multiple (over eight covariates) adjusted effect estimates from a single model in Table 3. The findings present in Table 3 may mix direct and total effect of each variable and make interpretation difficult2. Specifically, in current study, the authors aimed to assess the total effect of COVID-19 vaccination (the primary exposure) on the odds of gout flare while adjusting for other potential confounders3. Thus, the odds ratios for other covariates (e.g. colchicine prophylaxis treatment) are likely to reflect the direct effect of each covariate rather than total effect, and such a direct effect may be biased due to potential selection bias 4. For example, the odds ratio of sex increased dramatically from 0.82 in univariate analysis to 4.33 in model 2 analysis, which was biologically controversial.
Second, the calculation of odds ratios for vaccination and its subgroups in Table 3 seems questionable. Using the same reference group (no vaccination), the odds ratio of gout flares for any COVID-19 vaccines was 4.57 (p< 0.001), for subgroup of Sinovac Life vaccine was 2....
We read with great interest the article titled ‘Colchicine prophylaxis is associated with fewer gout flares after COVID-19 vaccination’ by Lu et al.1. The authors found that COVID-19 vaccination was associated with increased odds of gout flare and was negatively associated with colchicine prophylaxis. However, we would like to draw attention to some concerns.
First, it is problematic to present multiple (over eight covariates) adjusted effect estimates from a single model in Table 3. The findings present in Table 3 may mix direct and total effect of each variable and make interpretation difficult2. Specifically, in current study, the authors aimed to assess the total effect of COVID-19 vaccination (the primary exposure) on the odds of gout flare while adjusting for other potential confounders3. Thus, the odds ratios for other covariates (e.g. colchicine prophylaxis treatment) are likely to reflect the direct effect of each covariate rather than total effect, and such a direct effect may be biased due to potential selection bias 4. For example, the odds ratio of sex increased dramatically from 0.82 in univariate analysis to 4.33 in model 2 analysis, which was biologically controversial.
Second, the calculation of odds ratios for vaccination and its subgroups in Table 3 seems questionable. Using the same reference group (no vaccination), the odds ratio of gout flares for any COVID-19 vaccines was 4.57 (p< 0.001), for subgroup of Sinovac Life vaccine was 2.90 (p= 0.011), and for Sinopharm BIBP vaccine and other vaccines were 0.55 (p= 0.09) and 0.70 (p= 0.32), respectively. Of note, Sinopharm BIBP and other vaccines cases accounted for 45.9% of all COVID-19 vaccines assessed in this study as shown in Table 1. One would expect that the odds ratio of gout flare for any COVID-19 vaccines should be less than 2.90 (i..e, the odds ratio of gout flares for Sinovac Life vaccine). Using results provided in Table 1 and Table 2, we recalculated the crude odds ratio of gout flares for any COVID-19 vaccines (i.e., Sinovac Life vaccine, Sinopharm BIBP vaccine, and other vaccines combined), the odds ratio of gout flares was 1.65, not 4.57, suggesting either effect estimate for any COVID-19 vaccines or effect estimates for subgroups of vaccines may be incorrect.
To sum up, the concerns regarding “Table 2 Fallacy” and miscalculations of effect sizes in Table 3 should be taken into consideration to make this study more convincing and validating. We appreciate the work done by the authors and are looking forward to their responses.
Ethics statements: Not required.
Patient consent for publication: Not required.
Conflict of Interest Disclosures: None reported.
Contributors: TF, PC and ZZ drafted this correspondence. YL, MZ and SC were involved in revising and editing the correspondence.
Funding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Patient and public involvement: Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review: Not commissioned; internally peer reviewed
References
1. Lu J, He Y, Terkeltaub R, et al. Colchicine prophylaxis is associated with fewer gout flares after COVID-19 vaccination. Ann Rheum Dis 2022 doi: 10.1136/annrheumdis-2022-222199 [published Online First: 2022/03/13]
2. Westreich D, Greenland S. The table 2 fallacy: presenting and interpreting confounder and modifier coefficients. Am J Epidemiol 2013;177(4):292-8. doi: 10.1093/aje/kws412 [published Online First: 2013/02/02]
3. Robins JM, Greenland S. Identifiability and exchangeability for direct and indirect effects. Epidemiology 1992;3(2):143-55. doi: 10.1097/00001648-199203000-00013 [published Online First: 1992/03/01]
4. Hernan MA, Hernandez-Diaz S, Werler MM, et al. Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol 2002;155(2):176-84. doi: 10.1093/aje/155.2.176 [published Online First: 2002/01/16]
5. Susser ES, S.; Morabia, A,; Bromet, E, J. . Psychiatric epidemiology 2006
6. Szklo M. Population-based cohort studies. Epidemiol Rev 1998;20(1):81-90. doi: 10.1093/oxfordjournals.epirev.a017974 [published Online First: 1998/10/08]
7. Schwartz S, Campbell UB, Gatto NM, et al. Toward a Clarification of the Taxonomy of "Bias" in Epidemiology Textbooks. Epidemiology 2015;26(2):216-22. doi: 10.1097/Ede.0000000000000224
We read the study by Fagni F et al. on the possible therapeutic effect of secukinumab for Behçet’s syndrome (BS).1 Fifteen BS patients with active mucosal and articular phenotypes participated in their study. Patients with polyarthritis started secukinumab at 300 mg/month; others initially received 150 mg/month, with dosage and frequency adjusted in patients responding poorly. After three months of follow-up, 9 (66.7%) patients achieved a partial or complete response; this proportion increased to 86.7% at six months and 100% at 24 months. The initial dose of 300 mg/month indicated a better therapeutic effect. As for the control of mucosal ulcers, the median number of oral ulcers in the last 28 days decreased significantly from 2 to 1 at three months and 0 at six months, indicating a promising effect of secukinumab for mucosal ulcers. Here, we report the efficacy and safety of secukinumab on refractory mucosal BS in the Chinese population.
We enrolled six BS patients (two males and four females), fulfilling the 2013 International Criteria for BS, between October 2020 and March 2022 with a mean age of 33.8 ± 6.6 years and a median disease duration of 8 (IQR 3,10) years. At enrolment, they all presented with active oral/genital ulcers that responded inadequately to or were intolerant to conventional therapies or biologics. The combined immunosuppressants/immunomodulators were maintained for at least two or three months before evaluating their effectiveness; otherwise,...
We read the study by Fagni F et al. on the possible therapeutic effect of secukinumab for Behçet’s syndrome (BS).1 Fifteen BS patients with active mucosal and articular phenotypes participated in their study. Patients with polyarthritis started secukinumab at 300 mg/month; others initially received 150 mg/month, with dosage and frequency adjusted in patients responding poorly. After three months of follow-up, 9 (66.7%) patients achieved a partial or complete response; this proportion increased to 86.7% at six months and 100% at 24 months. The initial dose of 300 mg/month indicated a better therapeutic effect. As for the control of mucosal ulcers, the median number of oral ulcers in the last 28 days decreased significantly from 2 to 1 at three months and 0 at six months, indicating a promising effect of secukinumab for mucosal ulcers. Here, we report the efficacy and safety of secukinumab on refractory mucosal BS in the Chinese population.
We enrolled six BS patients (two males and four females), fulfilling the 2013 International Criteria for BS, between October 2020 and March 2022 with a mean age of 33.8 ± 6.6 years and a median disease duration of 8 (IQR 3,10) years. At enrolment, they all presented with active oral/genital ulcers that responded inadequately to or were intolerant to conventional therapies or biologics. The combined immunosuppressants/immunomodulators were maintained for at least two or three months before evaluating their effectiveness; otherwise, they were discontinued due to adverse effects. Also, case 1 met the criteria for SAPHO (synovitis-acne-pustulosis-hyperostosis-osteitis) syndrome, and cases 3 and 4 met axial-spondyloarthritis (ax-SpA) criteria. Two patients (cases 1 and 3) received prophylaxis for latent tuberculosis. Secukinumab was administered subcutaneously at 150 mg/week in the first month and then 150 mg every 2-4 weeks, while concurrent glucocorticoids (GCs) and immunosuppressants/immunomodulators were maintained or tapered. The patients were followed up every 2-3 months; complete response (CR) for mucosal control was defined as no oral ulcer in the 28 days before the evaluation, and partial response (PR) was defined as a 50% or more reduction in the number of oral ulcers, and non-responders (NR) was defined as all other patients. 2
After three months of secukinumab treatment, cases 1, 2, and 3 achieved CR or PR, with BDCAF score improved (case 1 changed from 4 to 1, case 2 from 1 to 0, and case 3 from 3 to 1). In particular, Case 1 also had marked improvement in palmoplantar pustulosis. Cases 1 and 2 maintained CR or PR during the entire follow-up of 15 and 12 months, respectively. Case 3 was free of lower back pain one month after stating secukinumab but had a severe relapse in the eighth month with multiple oropharyngeal ulcers, gastric antrum erosion, and proctitis, which was resolved after switching to etanercept. On the other hand, three patients (cases 4, 5, and 6) showed no response after two months of secukinumab treatment, and case 4 newly developed fevers, multiple erosions, and ulcers in the esophagus, stomach, and colon. Although Fagni F et al. reported that secukinumab remarkably controlled gastrointestinal (GI) BS symptoms in 9 patients and significantly reduced fecal calprotectin (FC) levels in 4 out of 9 patients. Our report showed that BS patients with refractory mucosal lesions had heterogeneous responses to secukinumab and adverse effects on the GI tract that could not be ignored.
Secukinumab, a monoclonal anti-IL-17A antibody, is currently proven efficacious in treating active psoriatic arthritis and ankylosing spondylitis.3 Accordingly, we observed satisfactory response in BS patients with ax-SpA and palmoplantar pustulosis. Although growing evidence indicates that IL-17A and IL-17A-producing Th17 cells contribute to the pathogenesis of BS, the subgroup of BS patients that may benefit from secukinumab remains debatable. In addition to the report by Fagni F et al., we recently showed that secukinumab might be effective for patients with parenchymal Neuro-BS.4 Unexpectedly, it failed to demonstrate superiority to placebo in treating Behçet’s uveitis.5 Together, the various etiology and heterogeneity of BS phenotypes might explain the different responses to secukinumab.
IL-17A is a crucial mediator of inflammation. While dysregulated IL-17A production promotes pathogenic inflammation, local IL-17A is essential for microbial clearance and mucosal barrier maintenance.6 Firstly, IL-17A promotes the secretion of chemokines such as CXCL1 and CXCL8, which attract neutrophils as a defense against microbes. Secondly, IL-17A promotes the expression of antimicrobial peptides that protect the host during the acute phase of fungal and bacterial infection. Finally, IL-17A in the intestine promotes tight-junction protein expression,6 which helps maintain the integrity of intestinal mucosa during inflammation. Dysbiosis of oral and gut microbiomes was reported in BS patients, particularly with reduced diversity of the gut microbial community and an enriched abundance of opportunistic pathogens.7 Collectively, inhibiting IL-17A might sabotage its potential protective effects, which may explain the non-responders and two patients (cases 3 and 4) who developed GI ulcers during treatment. Coincidentally, Secukinumab was ineffective in treating Crohn’s disease (CD) and showed a higher incidence of fungal infections than placebo.8 And BS-like lesions such as oral/genital ulcers were observed in psoriasis (Ps) patients receiving secukinumab.9 Using secukinumab for Ps and SpA patients resulted in new-onset inflammatory bowel disease and the exacerbation of CD.10 These raise concerns that direct IL-17A inhibition could disrupt its gut-protective capacity, which might be exacerbated by specific dysbiosis in BS. Therefore, BS patients receiving secukinumab should be closely monitored for adverse effects on the GI tract.
In conclusion, our study of secukinumab on BS mucosal involvement did not come out as expected, with half of the patients responding poorly. Furthermore, secukinumab-associated GI adverse effects were firstly reported in BS patients, suggesting that the mechanism of local IL-17A signaling remained elusive. Further discussion of IL-17A inhibition in BS is warranted.
Acknowledgements We thank all the patients who participated in this study.
Competing interests: None declared.
Patient and public involvement: Patients and the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Ethics approval: Institutional review board of Peking Union Medical College Hospital.
REFERENCES
1. Fagni F, Bettiol A, Talarico R, et al. Long-term effectiveness and safety of secukinumab for treatment of refractory mucosal and articular Behçet's phenotype: a multicentre study. Annals of the Rheumatic Diseases. 2020; 79(8):1098-104.
2. Mirouse A, Barete S, Monfort JB, et al. Ustekinumab for Behcet's disease. J Autoimmun. 2017; 82:41-46.
3. Garcia-Montoya L, Marzo-Ortega H. The role of secukinumab in the treatment of psoriatic arthritis and ankylosing spondylitis. Ther Adv Musculoskelet Dis. 2018; 10(9):169-80.
4. Liu J, Tian J, Wang Z, et al. Secukinumab in the treatment of parenchymal neuro-Behçet's syndrome. Rheumatology (Oxford, England). 2022:keac222.
5. Ozguler Y, Ozdede A, Hatemi G. Recent Insights into the Management of Behçet Syndrome. J Inflamm Res. 2021; 14:3429-41.
6. McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 Family of Cytokines in Health and Disease. Immunity. 2019; 50(4):892-906.
7. Mehmood N, Low L, Wallace GR. Behçet's Disease-Do Microbiomes and Genetics Collaborate in Pathogenesis? Frontiers in Immunology. 2021; 12:648341.
8. Hueber W, Sands BE, Lewitzky S, et al. Secukinumab, a human anti-IL-17A monoclonal antibody, for moderate to severe Crohn's disease: unexpected results of a randomised, double-blind placebo-controlled trial. Gut. 2012; 61(12):1693-700.
9. Dincses E, Yurttas B, Esatoglu SN, et al. Secukinumab induced Behcet's syndrome: a report of two cases. Oxf Med Case Reports. 2019; 2019(5):omz041.
10. Blair HA. Secukinumab: A Review in Ankylosing Spondylitis. Drugs. 2019; 79(4):433-43.
Ugarte-Gil, et al (1) recently published a study reporting several characteristics associated with severe COVID-19 outcomes in people with systemic lupus erythematosus(SLE). Demographic factors, comorbidities, active or untreated SLE, and patients treated with glucocorticoids were the most noticeable features. Even though several covariates had been taken into consideration to minimize the impacts of these confounders, we presume vaccination could play a crucial role in the COVID-19 outcomes.
Previous studies had pointed out the protective effect that vaccination could provide against poor outcomes in the general population (2). In spite of a lack of evidence on the efficacy of COVID-19 vaccines in patients with SLE, achieving adequate sero-protection after receiving COVID-19 vaccine could be expected according to the expert opinion based on the knowledge on the use of other vaccines in this specific group of patients (3). A review article published by Wei Tang, et al (4) showed that commonly used immunosuppressants inclusive of glucocorticoids, methotrexate, mycophenolate mofetil/mycophenolic acid and rituximab might impede vaccine responses, causing less sufficient immune responses after getting COVID-19 vaccines in SLE patients. Hence, we suggest a subgroup analysis according to whether being vaccinated or not to have better data interpretation and to clarify the possible factors that may lead to critical consequences in SLE patients infected with COVID-19. ...
Ugarte-Gil, et al (1) recently published a study reporting several characteristics associated with severe COVID-19 outcomes in people with systemic lupus erythematosus(SLE). Demographic factors, comorbidities, active or untreated SLE, and patients treated with glucocorticoids were the most noticeable features. Even though several covariates had been taken into consideration to minimize the impacts of these confounders, we presume vaccination could play a crucial role in the COVID-19 outcomes.
Previous studies had pointed out the protective effect that vaccination could provide against poor outcomes in the general population (2). In spite of a lack of evidence on the efficacy of COVID-19 vaccines in patients with SLE, achieving adequate sero-protection after receiving COVID-19 vaccine could be expected according to the expert opinion based on the knowledge on the use of other vaccines in this specific group of patients (3). A review article published by Wei Tang, et al (4) showed that commonly used immunosuppressants inclusive of glucocorticoids, methotrexate, mycophenolate mofetil/mycophenolic acid and rituximab might impede vaccine responses, causing less sufficient immune responses after getting COVID-19 vaccines in SLE patients. Hence, we suggest a subgroup analysis according to whether being vaccinated or not to have better data interpretation and to clarify the possible factors that may lead to critical consequences in SLE patients infected with COVID-19.
Interestingly, the ordinal regression models examining the association between medication usage and disease severity of COVID-19 in this study revealed more favorable outcomes when SLE was treated with belimumab (1). A meta-analysis conducted by Singh et al (5) concluded six randomized controlled trials that belimumab showed clinically significant efficacy in comparison with placebo in participants with SLE at 52 weeks. Taken together with the better COVID-19 outcomes in patients using belimumab in the present study and evidence regarding the promising results of belimumab provided by former studies, we regard belimumab may be a potential direction for future research in SLE patients infected with COVID-19.
(1) Ugarte-Gil, M.F., Alarcón, G.S., Izadi, Z., et al. 2022. Characteristics associated with poor COVID-19 outcomes in individuals with systemic lupus erythematosus: data from the COVID-19 Global Rheumatology Alliance. Annals of the Rheumatic Diseases annrheumdis–202. doi:10.1136/annrheumdis-2021-221636
(2) Tartof, S.Y., Slezak, J.M., Fischer, et al. 2021. Effectiveness of mRNA BNT162b2 COVID-19 vaccine up to 6 months in a large integrated health system in the USA: a retrospective cohort study. The Lancet 398, 1407–1416. doi:10.1016/s0140-6736(21)02183-8
(3) Mason, A., Anver, H., Lwin, et al. 2021. Lupus, vaccinations and COVID-19: What we know now. Lupus 30, 1541–1552.doi:10.1177/09612033211024355
(4) Tang, W., Gartshteyn, Y., Ricker, E., et al. 2021. The Use of COVID-19 Vaccines in Patients with SLE. Current Rheumatology Reports 23. doi:10.1007/s11926-021-01046-2
(5) Singh JA, Shah NP, Mudano AS.2021. Belimumab for systemic lupus erythematosus. Cochrane Database Syst Rev. 2021 Feb 25;2(2):CD010668. doi: 10.1002/14651858.CD010668
We really appreciated the results of the exploratory study by Hakroush and colleagues, which provides further insights into the potential role of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with lupus nephritis and renal vasculitis.1 Unfortunately, at present, relevant clinical evidence is missing.
It has been formerly known that focal segmental glomerulosclerosis (FSGS) is considered as a distinct phenotype of lupus podocytopathy, which is associated with a severe tubulo-interstitial injury and a much lower complete remission rate, compared to other phenotypes, such as mimimal change and mesangial proliferation.2,3
According to a recently published, post-hoc analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin compared to placebo resulted in a lower mean rate of estimated glomerular filtration rate decline among patients with baseline FSGS, although the result was not statistically significantly, possibly due to the small number of patients with FSGS (n = 104).4 Results of the EMPA-KIDNEY trial, which are anticipated within 2022, will provide more definitive answers on whether SGLT-2 inhibitors can play a crucial role in the therapeutic management of lupus nephritis the next years.5
References
1. Hakroush S, Tampe D, Kluge IA, Baier E, Korsten P, Tampe B. Comparative analysis of SGLT-2 expression in renal vasculitis and lupus nephritis. Ann Rheum Dis. 2022...
We really appreciated the results of the exploratory study by Hakroush and colleagues, which provides further insights into the potential role of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with lupus nephritis and renal vasculitis.1 Unfortunately, at present, relevant clinical evidence is missing.
It has been formerly known that focal segmental glomerulosclerosis (FSGS) is considered as a distinct phenotype of lupus podocytopathy, which is associated with a severe tubulo-interstitial injury and a much lower complete remission rate, compared to other phenotypes, such as mimimal change and mesangial proliferation.2,3
According to a recently published, post-hoc analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin compared to placebo resulted in a lower mean rate of estimated glomerular filtration rate decline among patients with baseline FSGS, although the result was not statistically significantly, possibly due to the small number of patients with FSGS (n = 104).4 Results of the EMPA-KIDNEY trial, which are anticipated within 2022, will provide more definitive answers on whether SGLT-2 inhibitors can play a crucial role in the therapeutic management of lupus nephritis the next years.5
References
1. Hakroush S, Tampe D, Kluge IA, Baier E, Korsten P, Tampe B. Comparative analysis of SGLT-2 expression in renal vasculitis and lupus nephritis. Ann Rheum Dis. 2022 Feb 25:annrheumdis-2022-222167. doi: 10.1136/annrheumdis-2022-222167. Epub ahead of print.
2. Hu W, Chen Y, Wang S, et al. Clinical-Morphological Features and Outcomes of Lupus Podocytopathy. Clin J Am Soc Nephrol 2016;11:585-92. doi:10.2215/CJN.06720615
3. Chen D, Hu W. Lupus podocytopathy: a distinct entity of lupus nephritis. J Nephrol 2018;31:629-34. doi:10.1007/s40620-017-0463-1
4. Wheeler DC, Jongs N, Stefansson BV, et al. Safety and efficacy of dapagliflozin in patients with focal segmental glomerulosclerosis: A prespecified analysis of the DAPA-CKD trial [published online ahead of print, 2021 Nov 25]. Nephrol Dial Transplant 2021;gfab335. doi:10.1093/ndt/gfab335
5. EMPA-KIDNEY Collaborative Group . Design, recruitment, and baseline characteristics of the EMPA-KIDNEY trial [published online ahead of print, 2022 Mar 3]. Nephrol Dial Transplant 2022;gfac040. doi:10.1093/ndt/gfac040
We thank Patoulias and colleagues for pointing out the relevance of clinical studies for the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in renal vasculitis and lupus nephritis.1 As discussed recently, relevant clinical evidence is missing because patients with autoimmune diseases were excluded from most renal outcome trials for SGLT-2 inhibitors.2-4 An exception for the use of SGLT-2 inhibitors in renal autoimmune diseases is the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial (DAPA-CKD, ClinicalTrials.gov Identifier: NCT03036150).5 In DAPA-CKD, the researchers evaluated the effects of SGLT-2 inhibitor dapagliflozin, along with angiotensin-blocking agents, on the progression of CKD, including those with immunoglobulin A nephropathy (IgAN).5 Overall, a 39% reduction in the primary outcome (≥50% decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes) was observed.5 Interestingly, patients with IgAN showed an unprecedented 71% reduction in the primary outcome, suggesting that CKD treatment may be equally beneficial in renal autoimmune diseases once the initial phase of remission induction is achieved and kidney function stabilized.6 Patients with renal vasculitis and lupus nephritis have a significantly increased risk for cardiovascular morbidity and mortality, with both inflammation and long-term use of immunosuppressants contributing to this risk.2 Therefore, SGLT-2 inhibitors could ultimately...
We thank Patoulias and colleagues for pointing out the relevance of clinical studies for the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in renal vasculitis and lupus nephritis.1 As discussed recently, relevant clinical evidence is missing because patients with autoimmune diseases were excluded from most renal outcome trials for SGLT-2 inhibitors.2-4 An exception for the use of SGLT-2 inhibitors in renal autoimmune diseases is the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial (DAPA-CKD, ClinicalTrials.gov Identifier: NCT03036150).5 In DAPA-CKD, the researchers evaluated the effects of SGLT-2 inhibitor dapagliflozin, along with angiotensin-blocking agents, on the progression of CKD, including those with immunoglobulin A nephropathy (IgAN).5 Overall, a 39% reduction in the primary outcome (≥50% decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes) was observed.5 Interestingly, patients with IgAN showed an unprecedented 71% reduction in the primary outcome, suggesting that CKD treatment may be equally beneficial in renal autoimmune diseases once the initial phase of remission induction is achieved and kidney function stabilized.6 Patients with renal vasculitis and lupus nephritis have a significantly increased risk for cardiovascular morbidity and mortality, with both inflammation and long-term use of immunosuppressants contributing to this risk.2 Therefore, SGLT-2 inhibitors could ultimately contribute to organ protection in renal autoimmune diseases by reducing CKD progression and cardiovascular risk.2 Results of the Study of Heart and Kidney Protection With Empagliflozin trial (EMPA-KIDNEY, ClinicalTrials.gov Identifier: NCT03594110) are anticipated within 2022, and will provide one step towards a more definitive answers on whether SGLT-2 inhibitors are relevant in the therapeutic management of renal autoimmune diseases, including lupus nephritis.7
References
1. Hakroush S, Tampe D, Kluge IA, et al. Comparative analysis of SGLT-2 expression in renal vasculitis and lupus nephritis. Ann Rheum Dis 2022 doi: 10.1136/annrheumdis-2022-222167 [published Online First: 2022/02/27]
2. Saemann M, Kronbichler A. Call for action in ANCA-associated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors. Ann Rheum Dis 2021 doi: 10.1136/annrheumdis-2021-221474 [published Online First: 2021/12/01]
3. Patoulias D. Correspondence on 'Call for action in ANCA-associated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors' by Saemann and Kronbichler. Ann Rheum Dis 2022 doi: 10.1136/annrheumdis-2021-221953 [published Online First: 2022/01/15]
4. Saemann M, Kronbichler A. Response to: Correspondence on 'Call for action in ANCA-associated vasculitis and lupus nephritis: promises and challenges of SGLT-2 inhibitors' by Saemann and Kronbichler. Ann Rheum Dis 2022 doi: 10.1136/annrheumdis-2021-221982 [published Online First: 2022/01/15]
5. Heerspink HJL, Stefansson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2020;383(15):1436-46. doi: 10.1056/NEJMoa2024816 [published Online First: 2020/09/25]
6. Wheeler DC, Toto RD, Stefansson BV, et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int 2021;100(1):215-24. doi: 10.1016/j.kint.2021.03.033 [published Online First: 2021/04/21]
7. Group E-KC. Design, recruitment, and baseline characteristics of the EMPA-KIDNEY trial. Nephrol Dial Transplant 2022 doi: 10.1093/ndt/gfac040 [published Online First: 2022/03/04]
We read with interest the study by Dr. Tedeschi and colleagues [1] which reported that patients with at least one episode of acute Calcium pyrophosphate (CPP) crystal arthritis had increased the risk of short (0-2 year) and long-term (2-10 year) non-fatal CV events compared with those without evidence of this acute crystalline arthritis. However, acute CPP crystal arthritis did not confer increased risk for all-cause mortality. This study focuses on an episode of acute calcium pyrophosphate (CPP) crystal arthritis as a significant clinical variable and is a valuable addition to the literature. However, some issues have not been addressed by the authors.
Show MoreFirst, epidemiologists agree that several clinical risk factors are associated with cardiovascular outcome, including acute cerebrovascular insufficiency, hyperparathyroidism, and phenotypes of CPP disease [2,3]. However, the authors did not exclude people with these risk factors, and an evaluation of these risk factors was not presented. The confounding effect of these variables may have contributed to the significant effect in causing cardiovascular disease.
Second, it reported that longer disease duration of CPP crystal arthritis have also been considered to carry an elevated risk for cardiovascular disease [4]. Previous studies have clearly demonstrated that chronic CPP crystal arthritis did confer increased risk for myocardial infarction, acute coronary syndrome, and stroke[5]. However, the duration of CPP...
To the Editor
Show MoreWe recently have read the article written by Dr. Daien et al. entitled published in Annals of the Rheumatic Diseases in 31th of May, 2022 (1). The study assessed the effect of different doses of ABX464 on clinical and laboratory features of patients with active rheumatoid arthritis (RA) and the rate of development of treatment-emergent adverse events in these patients. In this study, it was showed that each day 50 mg use of ABX464 could exert beneficial effects in the patients with acceptable safety and tolerability profile. This study provides fascinating evidence regarding the use of this first-in-class drug candidate for patients not responding to more frequently used treatment regimens; however, there are some points that we would like to address.
The authors mentioned that patients with moderate to severe RA who had rheumatoid factor, anticitrullinated peptide antibody or bone erosions were recruited in the study. The study aimed at comparison of rate of response to the treatment and development of adverse events in each arm of the study. Although, it is generally considered that the randomized design of the clinical studies would produce comparable groups and result in unbiased assessment of the outcomes, different factors which were previously identified in the literature that could be in association with severity of rheumatoid arthritis or poor response to the treatment should had been considered in the quantitative analysis of this study....
Glucocorticoid (GC) therapy is still the mainstay in managing rheumatoid arthritis (RA). The benefits of low-dose GC therapy are well established after decades of clinical experience in RA. Yet, it is essential to appoint the danger of exposure to chronic GC therapy.
Show MoreFor many patients with RA and other inflammatory rheumatic musculoskeletal diseases (RMD), starting prednisolone means taking glucocorticoids for several years or decades, often indefinitely.1 The long-term complications of GC therapy are rarely emphasised by most clinical trials that usually run for only 1 or 2 years. In this regard, the GLORIA trial2 has illuminated both the harms and benefits of 2-year low-dose (5 mg daily) prednisolone in 451 elderly patients (≥65 years) with moderately active established RA. Indeed, there was an 11% increase in patients with at least one adverse event (AE) of special interest (mainly mild to moderate infections) in the prednisolone arm, accounting for a 1.24 (95% CL 0.4) fold higher risk compared to placebo, just within two years of treatment.2
The likelihood of major osteoporotic fractures in GC users increases with the dosage, but more importantly, with the cumulative dose and duration of GC therapy.3 Moreover, low-dose GC therapy (≤5 mg/day) did not seem to be associated with a reduction of bone mineral density (BMD) in patients with inflammatory RMD and current or prior exposure to GC.4 However, while GC therapy effectively alleviates inflammation, it has...
Bandak et al.[1] recently published a paper comparing the effect of an exercise and education program with an open-label placebo on a range of outcomes for people with knee osteoarthritis (OA). The exercise and education program consisted of two weeks of 1x1.5 hour education sessions/ week, then six weeks of 2x1 hour exercise sessions/ week. The open-label placebo involved four fortnightly knee intra-articular saline injections and arthrocentesis (if required).[1] The authors argued “open-label placebo provides an opportunity to compare exercise and education with an inert comparator and thereby mitigate some of the inbuilt challenges with blinded comparator groups in clinical trials of exercise and education.” However, the use of an open-label placebo does not attempt to facilitate any opportunity for blinding, and their ‘placebo’ intervention does not meet established placebo criteria.
Placebo interventions should have no therapeutic effect, and should be perceived to be identical to the intervention of interest,[2] to control for the placebo effect; neither of these criteria has been met by Bandak et al.’s[1] placebo. Although saline injections are pharmacologically inert, they may have a real therapeutic effect particularly when coupled with arthrocentesis, as they may exert specific physical and chemical effects that could improve symptoms.[3] As such, it has been recommended that saline intra-articular injections not be used as placebo interventions in studi...
Show MoreThe Impact of Clinical Setting on ANA Responses in SLE: Comment on the article by Choi et al.
David S. Pisetsky1 2 and Peter E. Lipsky3 4
1 Medical Research Service, Durham VA Medical Center, Durham, North Carolina, USA
2 Departments of Medicine and Immunology, Duke University Medical Center, Durham, North Carolina, USA
3 RILITE Foundation, Charlottesville, Virginia, USA
4 AMPEL BioSolutions LLC, Charlottesville, Virginia, USA
In a recent paper in the Annals of the Rheumatic Diseases, Choi et al report data on the expression of antinuclear antibodies (ANA) in the sera of patients with systemic lupus erythematosus (SLE).(1) Using a large cohort of well characterized patients from the SLICC (Systemic Lupus International Cooperating Clinics) consortium, the authors show that ANA expression is almost invariable in SLE using three ANA assays (two immunofluorescence or IFA and one ELISA); over time, some changes can occur, with the ELISA showing a greater reduction in the frequency of positive responses than the IFA assays. In this study, patients were early in disease, with the first sample obtained on average 0.58 years after diagnosis.
Show MoreChoi et al are to be congratulated for this detailed and comprehensive study that includes longitudinal data. Most other studies on ANA expression in SLE have been cross-sectional in design or involved longitudinal data of relatively few patients.(2) Nevertheless, while consistent with data und...
We read with great interest the article titled ‘Colchicine prophylaxis is associated with fewer gout flares after COVID-19 vaccination’ by Lu et al.1. The authors found that COVID-19 vaccination was associated with increased odds of gout flare and was negatively associated with colchicine prophylaxis. However, we would like to draw attention to some concerns.
First, it is problematic to present multiple (over eight covariates) adjusted effect estimates from a single model in Table 3. The findings present in Table 3 may mix direct and total effect of each variable and make interpretation difficult2. Specifically, in current study, the authors aimed to assess the total effect of COVID-19 vaccination (the primary exposure) on the odds of gout flare while adjusting for other potential confounders3. Thus, the odds ratios for other covariates (e.g. colchicine prophylaxis treatment) are likely to reflect the direct effect of each covariate rather than total effect, and such a direct effect may be biased due to potential selection bias 4. For example, the odds ratio of sex increased dramatically from 0.82 in univariate analysis to 4.33 in model 2 analysis, which was biologically controversial.
Second, the calculation of odds ratios for vaccination and its subgroups in Table 3 seems questionable. Using the same reference group (no vaccination), the odds ratio of gout flares for any COVID-19 vaccines was 4.57 (p< 0.001), for subgroup of Sinovac Life vaccine was 2....
Show MoreWe read the study by Fagni F et al. on the possible therapeutic effect of secukinumab for Behçet’s syndrome (BS).1 Fifteen BS patients with active mucosal and articular phenotypes participated in their study. Patients with polyarthritis started secukinumab at 300 mg/month; others initially received 150 mg/month, with dosage and frequency adjusted in patients responding poorly. After three months of follow-up, 9 (66.7%) patients achieved a partial or complete response; this proportion increased to 86.7% at six months and 100% at 24 months. The initial dose of 300 mg/month indicated a better therapeutic effect. As for the control of mucosal ulcers, the median number of oral ulcers in the last 28 days decreased significantly from 2 to 1 at three months and 0 at six months, indicating a promising effect of secukinumab for mucosal ulcers. Here, we report the efficacy and safety of secukinumab on refractory mucosal BS in the Chinese population.
We enrolled six BS patients (two males and four females), fulfilling the 2013 International Criteria for BS, between October 2020 and March 2022 with a mean age of 33.8 ± 6.6 years and a median disease duration of 8 (IQR 3,10) years. At enrolment, they all presented with active oral/genital ulcers that responded inadequately to or were intolerant to conventional therapies or biologics. The combined immunosuppressants/immunomodulators were maintained for at least two or three months before evaluating their effectiveness; otherwise,...
Show MoreUgarte-Gil, et al (1) recently published a study reporting several characteristics associated with severe COVID-19 outcomes in people with systemic lupus erythematosus(SLE). Demographic factors, comorbidities, active or untreated SLE, and patients treated with glucocorticoids were the most noticeable features. Even though several covariates had been taken into consideration to minimize the impacts of these confounders, we presume vaccination could play a crucial role in the COVID-19 outcomes.
Show MorePrevious studies had pointed out the protective effect that vaccination could provide against poor outcomes in the general population (2). In spite of a lack of evidence on the efficacy of COVID-19 vaccines in patients with SLE, achieving adequate sero-protection after receiving COVID-19 vaccine could be expected according to the expert opinion based on the knowledge on the use of other vaccines in this specific group of patients (3). A review article published by Wei Tang, et al (4) showed that commonly used immunosuppressants inclusive of glucocorticoids, methotrexate, mycophenolate mofetil/mycophenolic acid and rituximab might impede vaccine responses, causing less sufficient immune responses after getting COVID-19 vaccines in SLE patients. Hence, we suggest a subgroup analysis according to whether being vaccinated or not to have better data interpretation and to clarify the possible factors that may lead to critical consequences in SLE patients infected with COVID-19.
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We really appreciated the results of the exploratory study by Hakroush and colleagues, which provides further insights into the potential role of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in patients with lupus nephritis and renal vasculitis.1 Unfortunately, at present, relevant clinical evidence is missing.
It has been formerly known that focal segmental glomerulosclerosis (FSGS) is considered as a distinct phenotype of lupus podocytopathy, which is associated with a severe tubulo-interstitial injury and a much lower complete remission rate, compared to other phenotypes, such as mimimal change and mesangial proliferation.2,3
According to a recently published, post-hoc analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial, dapagliflozin compared to placebo resulted in a lower mean rate of estimated glomerular filtration rate decline among patients with baseline FSGS, although the result was not statistically significantly, possibly due to the small number of patients with FSGS (n = 104).4 Results of the EMPA-KIDNEY trial, which are anticipated within 2022, will provide more definitive answers on whether SGLT-2 inhibitors can play a crucial role in the therapeutic management of lupus nephritis the next years.5
References
1. Hakroush S, Tampe D, Kluge IA, Baier E, Korsten P, Tampe B. Comparative analysis of SGLT-2 expression in renal vasculitis and lupus nephritis. Ann Rheum Dis. 2022...
Show MoreWe thank Patoulias and colleagues for pointing out the relevance of clinical studies for the use of sodium-glucose cotransporter-2 (SGLT-2) inhibitors in renal vasculitis and lupus nephritis.1 As discussed recently, relevant clinical evidence is missing because patients with autoimmune diseases were excluded from most renal outcome trials for SGLT-2 inhibitors.2-4 An exception for the use of SGLT-2 inhibitors in renal autoimmune diseases is the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial (DAPA-CKD, ClinicalTrials.gov Identifier: NCT03036150).5 In DAPA-CKD, the researchers evaluated the effects of SGLT-2 inhibitor dapagliflozin, along with angiotensin-blocking agents, on the progression of CKD, including those with immunoglobulin A nephropathy (IgAN).5 Overall, a 39% reduction in the primary outcome (≥50% decline in eGFR, end-stage kidney disease, or death from cardiovascular or renal causes) was observed.5 Interestingly, patients with IgAN showed an unprecedented 71% reduction in the primary outcome, suggesting that CKD treatment may be equally beneficial in renal autoimmune diseases once the initial phase of remission induction is achieved and kidney function stabilized.6 Patients with renal vasculitis and lupus nephritis have a significantly increased risk for cardiovascular morbidity and mortality, with both inflammation and long-term use of immunosuppressants contributing to this risk.2 Therefore, SGLT-2 inhibitors could ultimately...
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